Sirtuin‐mediated deacetylation pathway stabilizes Werner syndrome protein

Kahyo, Tomoaki; Mostoslavsky, Raúl; Goto, Makoto; Setou, Mitsutoshi

doi:10.1016/j.febslet.2008.06.031

Cited by 37 publications

(28 citation statements)

References 30 publications

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“…WRN, a nuclear protein mutated in WS, plays multiple roles in DNA metabolism including DNA replication, repair, and telomere maintenance [28]. In rats, calorie restriction-induced Sirt1 upregulation stabilizes and increases WRN in the liver [10]; however, there has been no previous study of the changes in WRN expression induced in ARF kidneys. In the present study, we first showed that WRN protein production is induced by 6 h after CDDP administration, after which the level remains high until at least 14 days later.…”

Section: Discussionmentioning

confidence: 99%

“…We first examined the association between histone H3 deacetylation and changes in HDAC3 (the Rdp-related class I), HDAC5 (the Hsa2-related class II) and the mammalian homolog of silent information regulator 2 (Sir2), so-called Sirt1 (class III) for 14 days after CDDP injection. Since Sirt1 also deacetylates non-histone proteins including p53, DNA repair proteins, and several signaling factors [7][8][9], we next examined whether increased Sirt was related to acetylated p53 and Werner syndrome protein (WRN), a well recognized DNA repair protein which is a target for Sirt1 deacetylation [10,11], in CDDP-induced acute renal failure (ARF). We finally examined whether the transfection of Sirt1 mitigates the CDDP-induced cellar damage in human embryonic kidney (HEK) 293 cells.…”

Section: Introductionmentioning

confidence: 99%

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Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

et al. 2011

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“…Immunoblotting Immunoblotting was performed as described previously (Kahyo et al, 2008). Briefly, the protein concentration of the lysate was measured with a BCA protein assay kit (Thermo Scientific, Rockford, IL, USA).…”

Section: Antibodiesmentioning

confidence: 99%

A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion

et al. 2011

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Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshinlike 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability.

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“…In our experiments, independent treatments of human fibroblasts with HU, MMS, MMC, and cisplatin did not influence the total level of endogenous WRN protein but caused 2–4 fold increases in the levels of WRN protein that was acetylated. Although other reports have noted that WRN stability and abundance correlates to its acetylation status (Li et al 2010; Vaitiekunaite et al 2007; Kahyo et al 2008), the lack of changes in total WRN levels in our experiments may be due to shorter time frames for most of our experiments and/or our measurement of endogenous WRN instead of ectopically expressed WRN. Treatment with UV-C irradiation (20 or 40 J/m 2 ), however, had no significant effect on the levels of acetylated WRN.…”

Section: Discussionmentioning

confidence: 60%

Acetylation of Werner syndrome protein (WRN): relationships with DNA damage, DNA replication and DNA metabolic activities

Lozada

Luo

et al. 2014

Biogerontology

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Loss of WRN function causes Werner Syndrome, characterized by increased genomic instability, elevated cancer susceptibility and premature aging. Although WRN is subject to acetylation, phosphorylation and sumoylation, the impact of these modifications on WRN’s DNA metabolic function remains unclear. Here, we examined in further depth the relationship between WRN acetylation and its role in DNA metabolism, particularly in response to induced DNA damage. Our results demonstrate that endogenous WRN is acetylated somewhat under unperturbed conditions. However, levels of acetylated WRN significantly increase after treatment with certain DNA damaging agents or the replication inhibitor hydroxyurea. Use of DNA repair-deficient cells or repair pathway inhibitors further increase levels of acetylated WRN, indicating that induced DNA lesions and their persistence are at least partly responsible for increased acetylation. Notably, acetylation of WRN correlates with inhibition of DNA synthesis, suggesting that replication blockage might underlie this effect. Moreover, WRN acetylation modulates its affinity for and activity on certain DNA structures, in a manner that may enhance its relative specificity for physiological substrates. Our results also show that acetylation and deacetylation of endogenous WRN is a dynamic process, with sirtuins and other histone deacetylases contributing to WRN deacetylation. These findings advance our understanding of the dynamics of WRN acetylation under unperturbed conditions and following DNA damage induction, linking this modification not only to DNA damage persistence but also potentially to replication stalling caused by specific DNA lesions. Our results are consistent with proposed metabolic roles for WRN and genomic instability phenotypes associated with WRN deficiency.

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Sirtuin‐mediated deacetylation pathway stabilizes Werner syndrome protein

Cited by 37 publications

References 30 publications

Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion

Acetylation of Werner syndrome protein (WRN): relationships with DNA damage, DNA replication and DNA metabolic activities

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